Study: H1N1 resistance to oseltamivir may spread

May 7, 2012 (CIDRAP News) – A detailed genetic analysis of an oseltamivir-resistant 2009 H1N1 virus responsible for a cluster of illnesses in Australia in 2011 found evidence that the viruses maintained their fitness when the resistance mutation was present, suggesting that widespread emergence of the strain may be more likely, according to the researchers.

During Australia's 2011 flu season, researchers identified 29 2009 H1N1 viruses containing the H275Y resistance mutation between May and October, and all were found in an analysis of patients from the country's Hunter New England region Most of the patients lived within 30 miles of Newcastle, and some had family or other contacts infected with the same strain . Only one of the patients had been treated with oseltamivir.

The team reported its most recent and detailed findings on the cluster in the May 4 edition of the Journal of Infectious Diseases.

The researchers first described the cluster in August 2011 in a post on ProMED Mail, the online reporting system of the International Society for Infectious Diseases. Four months later, they shared more detailed findings in a letter in the New England Journal of Medicine, which revealed that the virus appeared to be a single variant that was closely related to the vaccine strain and was also resistant to adamantanes but sensitive to zanamivir (Relenza). They warned that the changes bear watching and urged clinicians to be alert for similar clusters during the Northern Hemisphere flu season, which is just ending.

So far, testing of samples from the Northern Hemisphere's flu season has turned up few oseltamivir-resistant 2009 H1N1 viruses, though the US Centers for Disease Control and Prevention (CDC) said recently that 11 of 16 oseltamivir-resistant viruses this season so far have been from Texas, which has seen higher levels of 2009 H1N1 activity. The CDC said that though the level of oseltamivir-resistance in Texas was higher than for other states, it was still considered quite low.

The group based its latest findings on 29 viruses with oseltamivir resistance that were found among 191 2009 H1N1 viruses from the Hunter New England region that were tested from May through September 2011. The authors interviewed patients infected with the virus using a structured questionnaire to assess medical and antiviral treatment history.

They tested the samples for sensitivity to neuraminidase inhibitors, screened them for the H275Y mutation, constructed phylogenetic trees, and used computational structural analysis to assess protein stability changes associated with mutations.

They found that 26 of the 29 patients infected with resistant viruses lived in five adjacent downs, and three lived in rural towns located 90, 150, and 490 kilometers from Newcastle. For comparison, only five oseltamivir-resistant viruses containing the H275Y substitution were found during testing of 737 2009 H1N1 viruses in the rest of Australia during the 2011 flu season. Two were from hospitalized immunocompromised patients who were treated with oseltamivir in other states, and three were from otherwise healthy children who had not been treated with the drug. One patient from Perth, 4,000 kilometers west of Newcastle. None of the children or their families had traveled recently to Newcastle.

Genetic analysis revealed that the H275Y variants from all of the locations were virtually identical, suggesting that they emerged from a single source, the researchers reported.

The high frequency of oseltamivir resistance in patients with 2009 H1N1 infections who weren't treated with the drug suggests that the viruses are not less fit than sensitive ones, a scenario that is similar to the emergence of oseltamivir-resistant seasonal H1N1 viruses in Norway in 2007.

The group identified three neuraminidase mutations in the cluster isolates that they said could offset a destabilizing effect of the H275Y substitution: V241I, N369K, and N386S. They noted that two of the substitutions have also been seen in viral sequences from North American and Japanese oseltamivir-resistant H275Y strains.

The 2009 H1N1 virus might be becoming more tolerant of the H275Y mutation than when it first emerged, and widespread emergence of oseltamivir-resistant viruses may now be more likely, they wrote.

In an accompanying editorial, two virologists with the CDC's influenza division, Alicia Fry, MD, MPH, and Larisa Gubareva, MD, PhD, wrote that the rapid emergence of oseltamivir resistance in the former seasonal H1N1 virus in the 2008-09 flu season showed the importance of ongoing surveillance.

They wrote that so far it's unclear if the new H275Y 2009 H1N1 viruses have factors that give them an advantage over their susceptible counterparts.

Widespread circulation of a virus that is resistant to adamantanes and oseltamivir would have important implications for clinical care, Fry and Gubareva wrote. For example, inhaled zanamivir would be the only approved treatment in many countries, but it isn't an option for children younger than 7, those with underlying lung conditions, and those on mechanical ventilation. The intravenous form of the drug would be the treatment of choice for severely ill patients, but it is available only for experimental use and clinical trials.

Given the shortage of treatment options, it's important for researchers to learn more about drug resistance in 2009 H1N1 viruses, they wrote, noting that the Australian researchers found evidence suggesting that the virus in the Australian cluster might be less resistant to oseltamivir than resistant strains of the former seasonal H1N1 viruses were.

"This raises the question of whether oseltamivir might retain some clinical effectiveness against infections caused by H1N1pdm09 virus with the H275Y substitution and that oseltamivir might remain a treatment option, at least for persons without severe illness," Fry and Gubareva wrote.